The use of antimitotic agents as well as other drugs, is limited by their cardiotoxic action. Cardiotoxicity can be manifested by tachycardia, arrhythmias, dyspnea, hypotension, and congestive heart failure that is unresponsive to digitalis. The mortality rate associated with such cardiotoxicity is in excess of 50%. The use of several important therapeutic agents, including anti-cancer drugs such as the anthracycline antibiotic, adriamycin (doxorubicin), is hampered by these cardiotoxic effects.
The mechanism(s) of cardiac toxicity is complex. Several hypotheses have been formulated, including reduction of adriamycin to form a free radical (Bachur et al., 1977, Proc. Natl. Acad. Sci. U.S.A., 76:954-957) with subsequent generation of activated oxygen species (Goodman and Hochstein, 1977, Biochem. Biophys. Res. Commun., 77: 797-803) and lipid peroxidation (Mimnaugh et al., 1981, Toxicol. Appl. Pharmacol., 61: 313-315); alterations of mitochondrial respiration (Gonsalvez et al, 1974, Eur. J. Cancer, 10: 567-574) or Ca++ metabolism (Moore et al, 1977, Biochem. Med., 18: 131-138); and interaction with the mitochondrial lipid cardiolipin (Duarte-Karim, 1976, Biochem. Biophys. Res. Commun., 71: 658-663). It is possible that the mechanism is "multimodal", with several parallel actions being responsible (Tritton, 1991, Pharmac. Ther. 49:293-309).
Evaluation of possible cardiotoxicity is an important and necessary step during the development of new therapeutics and other agents. However, reliable, easy, and/or inexpensive screening methods to assess cardiotoxicity are lacking at the present time.
An assay is greatly needed to assess the potential cardiotoxicity of drugs and other compounds. The present invention is directed to this, as well as other, important ends.